Telomere Length Alterations Associated with Breast, Thyroid and Cervical Cancers

Zorawar Singh; Priya Khangotra

doi:10.18311/jhsr/2019/23361

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Original Article

4 (

); 10-15

doi:

10.18311/jhsr/2019/23361

Telomere Length Alterations Associated with Breast, Thyroid and Cervical Cancers

Zorawar Singh, Priya Khangotra

Department of Zoology, Khalsa College, Amritsar – 143001, Punjab, India

*Email: zorawarsinghs@rediffmail.com

Published: 2019-06-28

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This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0

Abstract

Telomeres are specialised structures of eukaryotic chromosomes that are present at each end of chromosomes. Telomeric length acts as a biological clock which helps to determine the life span of a cell and an organism. Telomeric shortening is also associated with various disease patterns including Dyskeratosis Congenita, Parkinson’s disease, Ulcerative Colitis and chronic hepatitis. Any anomality in the telomeric function initiates genomic instability which increases the risk of cancer. Individuals with short telomeres are at increased risk for cancer. This review paper aims to find out the studies pointing out the relation of telomeric length and different types of cancers including breast, thyroid and cervical cancer. A positive correlation has been found in between telomeric shortening and cancer occurrence. Further studies are suggested to strengthen the association of telomere length alterations with specific cancer type.

Keywords

Biomarker

Breast Cancer

Cervical Cancer

Telomere

Telomeric Shortening

Telomerase

Thyroid Cancer

Show Related Articles from PubMed

Introduction

Telomeres are specialised structures of eukaryotic chromosomes that are present at each end of chromosomes. Telomeres are TTAGGG tandem repeats capping chromosomal ends¹. The sequence of nucleotides is repeated approximately 1500 to 2000 times in human cells. Telomeres are essential for providing protection to genome from nucleolytic degradation and inter-chromosomal fusion. Telomeres also maintain the chromosomal and genomic stability². Telomerase is the enzyme that maintains the telomeric length by the addition of guanine rich repetitive sequences. Telomeric length acts as a biological clock which helps to determine the life span of a cell and an organism. The shortening of telomere length can be attributed to various reasons. Stress is one of the main causes of shortening of telomeres³. At high stress levels, function of telomerase is impaired and shortening of telomeres gets accelerated³. Smoking is the second reason for reduction in telomeric length. Obesity has also been found in correlation with increased oxidative stress, DNA damage and telomere shortening. An unbalanced dietary habit also enhances the telomere shortening.

Telomeric shortening is also associated with various disease patterns including Dyskeratosis Congenita (DC)⁴^,⁵, also known as Zinsser-Cole-Engman Syndrome, Parkinson’s disease, Ulcerative Colitis⁶ and chronic hepatitis⁷. Chronic Obstructive Pulmonary Disease (COPD)⁸^,⁹ and Type 2 diabetes¹⁰^–¹² have also been found related with telomeric shortening. Leukocyte Telomere Length (LTL) is a biological marker of aging and shorter LTL is associated with adverse cardiovascular outcomes¹³^–¹⁷. Telomere shortening was shown to parallel Alzheimer’s Disease (AD) associated dementia¹⁸. Various other studies also reported the association of telomere shortening and AD¹⁸^–²².

Telomeres as Biomarkers

Telomere alteration and telomerase activity have been observed in most human cancers and are known to be a feature of malignancy²³. Individuals with short telomeres are at an increased risk for cancer, since short telomeres lead to genomic instability²⁴. Hence, telomeres may act as biomarkers for the prediction and progression of a cancer type. The studies reporting the telomere length being associated in different cancer types are summarized below.

Breast Cancer

Breast cancer risk is affected by Telomere Length (TL). Telomere dysfunction plays a significant role in the initiation of genomic instability during carcinogenesis in human breast cancer²⁵. Working schedule may impact risk of breast cancer as TL is affected by intensive night work schedule. Working continuously for six consecutive nights for more than 5 years was found to decrease TL (-3.18, 95% CI: -6.46 TO -0.58, P = 0.016). There was a lower risk of breast cancer in nurses having longer TL, who worked more than four (OR: 0.37, 95% CI: 0.16 – 0.79, P = 0.014) or five (OR: 0.31, 95% CI: 0.10 – 0.83, P = 0.029) simultaneous night shifts for 5 years or more²⁶. In another study by Kammori et al.²⁷, a total of 44 breast cancer cases including 17 scirrhous, 15 papillotubular and 12 solid tubular carcinomas were investigated. Mean TL was found to be short in patients with large tumours, lymph node metastasis, vascular invasion and with third stage of tumour node metastasis. This data suggested the association of TL of cancer cells with the degree of cancer progression.

Genetic Polymorphisms in Breast Cancer

Several studies have reported an increase in breast cancer risk when patients are carriers of the CYP19 TTA polymorphism with > / = 10 repeats. In a study, a total of 180 postmenopausal healthy and 70 BC-diagnosed women were checked to understand the relationship between CYP19 TTA repetition polymorphism and telomere length. Patients with a BC diagnosis showed > 10 repetitions more frequently, compared with that of healthy women (50% vs. 23%, chi = 11.44, p = 0.0007)²⁸. IGFBP7 promoter methylation status was evaluated by methylation-specific PCR and its expression levels were determined by western blotting. A comparison was done between breast cancer tissues and adjacent normal tissues among Turkish women. GFBP7 methylation was observed in 90% of tumour tissues and 59% of controls (P = 0.0002)²⁹. Telomere dysfunction is known to activate ATM (Ataxia Telangiectasia Mutated)-mediated DNA damage response signalling pathways³⁰. ATM participates in the signalling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. Renault et al.³¹ measured mean TL and genotyped seven Single-nucleotide Polymorphisms (SNPs) recurrently associated with TL in large population-based studies. ATM mutation carriers (HetAT) individuals were found to be at increased risk of cancer (OR = 2.9, 95% CI = 1.2 – 4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95% CI = 1.2 – 7.1, P = 0.02), in comparison to their non- HetAT relatives. Similarly, knockdown of HMBOX1 was found associated with increased apoptosis rate and reduced expression of ATM³². The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. In a study, HMGA2 was found to prevent ATM-dependent pTRF2T188 phosphorylation and attenuate signalling via the telomere specific ATM-CHK2-CDC25C DNA damage signalling axis³³. High Mobility Group Box 1 (HMGB1) in tumour cells include replenishing telomeric DNA and maintaining cell immortality. Downregulation of HMGB1 modulated telomere homeostasis by changing the level of telomere-binding proteins, such as TPP1 (PTOP), TRF1 and TRF2. This downregulation also inhibited the ATM signalling pathways³⁴. In another study, the role of ATM-mediated DNA damage response signalling in Androgen Receptor (AR)-inactivated prostate cancer cells was investigated. The induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation of ATM. ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres³⁰.

Thyroid Cancer

Some studies have also been found reporting the association of TL and thyroid cancer³⁵^–³⁷. Human epidermal growth factor receptor 2 (HER2) proto-oncogene plays an important role in the development and progression of breast and gastric cancers. Amplification of HER 2 gene in differentiated thyroid cancer was found to be in correlation with telomere shortening²³. 69 cases of differentiated thyroid cancers were investigated. The telomeres of thyroid cancers, especially follicular carcinomas, were found to be significantly shorter than those of adjacent normal tissues²³. Similarly, the frequency of HER2 amplification, genetic variations in sporadic Papillary Thyroid Cancer (sPTC) and familial Papillary Thyroid Cancer (fPTC) and association with relative telomere length and BRAF mutational status were investigated. RTL was found to be shorter in fPTCs than sPTCs (p < 0.001) and HER2 amplification in fPTCs was found to be invariably associated with BRAF (V600E) mutation³⁸.

Cervical Cancer

Only a few studies reported the association of cervical cancer with telomere shortening. Various compounds may be involved in shortening of TL as Merghoub et al.³⁹ reported that tomentosin triggered telomere shortening and apoptosis in cervical cancer HeLa and SiHa cells. Similarly, Merghoub et al.⁴⁰ reported that the extracts from Inula viscosa L. target telomeres, induce apoptosis and overcome drug resistance in tumour cells. It was also found that extracts raised telomere shortening by suppressing the telomerase activity. Another study reported the association among HMBOX1, telomere length and radiosensitivity in cervical cancer cells. Knock-down of HMBOX1 was found to be associated with increased apoptosis rate and decreased expression of ATM, ATR, p-ATM, p-ATR and BRCA1⁴¹.

Table 1. Studies describing the association of telomere shortening with different cancer types

Author	Year	Type of cancer	Inference	Reference no.
Samulin et al.	2017	Breast cancer	Telomere shortening is associated with breast cancer risk in workers with long periods of consecutive night shifts.	42
Kammori et al.	2015	Breast cancer	Mean telomere length was found less in patients with TNM third stage; showed positive correlation with degree of cancer progression.	43
Cassar et al.	2017	Breast cancer	BMP7 induces breast cancer cell ageing by a mechanism involving BMPRII receptor-and Smad3- mediated repression of the hTERT gene.	44
Finot et al.	2017	Breast cancer	Genotoxic effect of ethyl paraben in the presence of S9 is associated with telomere shortening.	25
Sugishita et al.	2013	Thyroid cancer	Amplification of the human epidermal growth factor receptor 2 gene in differentiated thyroid cancer correlates with telomere shortening.	23
Merghoub et al.	2017	Cervical cancer	Tomentosin induced telomere shortening in cervical cancer cells in foetal fibroblast Wi38 and JW10 cells.	39
Merghoub et al.	2016	Cervical cancer	IV-HE and IV-DF extracts from Inula Viscosa L. induces telomere shortening and apoptosis in cervical cancer cells.	40
Zhou et al.	2017	Cervical cancer	Knockdown of HMBOX1 increases the radiosensitivity of cervical cancer cells through telomere shortening	41

qPCR - Quantitative Polymerase Chain Reaction; Q-FISH - Quantitative Fluorescence in-situ Hybridization; TNM - Tumour Node Metastasis; BMP7 - Bone Morphogenetic Protein-7; hTERT - Human Telomerase Reverse Transcriptase; MN - Micronucleus; FISH - Fluorescence in-situ Hybridization

Conclusion

Telomeric length determines the life span of a cell and an organism. Any change in telomeric function can result in genomic instability which in-turn increases the risk of cancer. Telomeric shortening is also associated with various disease patterns including Parkinson’s disease, ulcerative colitis and chronic hepatitis. Individuals with short telomeres are at increased risk for cancer. This paper reviewed the studies pointing out the relation of telomeric length and different types of cancers including breast, thyroid and cervical cancer. A positive correlation has been found in between telomeric shortening and cancer occurrence. Mean telomere lengths were found lesser in patients with cancer and showed a positive correlation with degree of cancer progression. Further correlative studies are recommended to strengthen the association of telomere length alterations with specific cancer type.

Conflict of Interest

None declared

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Introduction

Telomeres as Biomarkers

Breast Cancer

Genetic Polymorphisms in Breast Cancer

Thyroid Cancer

Cervical Cancer

Conclusion

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[1] Augustine TA, Baig M, Sood A, Budagov T, Atzmon G, Mariadason JM, Aparo S, Maitra R, Goel S. Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer. Br J Cancer. 2015;112:313-8. bjc2014561 [pii]
[CrossRef] [Google Scholar]

[2] Augustine T, Maitra R, Goel S. Telomere length regulation through epidermal growth factor receptor signaling in cancer. Genes Cancer. 2017;8:550-8.
[CrossRef] [Google Scholar]

[3] Biegler KA, Anderson AK, Wenzel LB, Osann K, Nelson EL. Longitudinal change in telomere length and the chronic stress response in a randomized pilot biobehavioral clinical study: Implications for cancer prevention. Cancer Prev Res (Phila). 2012;5:1173-82. 1940-6207.CAPR-12-0008 [pii]
[CrossRef] [Google Scholar]

[4] Frescas D, de LT. A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice. Genes Dev. 2014;28:153-66. 28/2/153 [pii]
[CrossRef] [Google Scholar]

[5] Lee JW. Telomere shortening by mutations in the RTEL1 helicase cause severe form of dyskeratosis congenita, HoyerallHreidarsson syndrome. Clin Genet. 2013;84:210.
[CrossRef] [Google Scholar]

[6] Friis-Ottessen M, Bendix L, Kolvraa S, Norheim-Andersen S, De Angelis PM, Clausen OP. Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis. BMC Gastroenterol. 2014;14:8. 1471-230X-14-8 [pii]
[CrossRef] [Google Scholar]

[7] Piciocchi M, Cardin R, Cillo U, Vitale A, Cappon A, Mescoli C, Guido M, Rugge M, Burra P, Floreani A, Farinati F. Differential timing of oxidative DNA damage and telo-mere shortening in hepatitis C and B virus-related liver carcinogenesis. Transl Res. 2016;168:122-33. S1931-5244(15)00298-4 [pii]
[CrossRef] [Google Scholar]

[8] Cordoba-Lanus E, Cazorla-Rivero S, Espinoza-Jimenez A, de-Torres JP, Pajares MJ, Aguirre-Jaime A, Celli B, Casanova C. Erratum to Telomere shortening and accelerated aging in COPD: Findings from the BODE cohort. Respir Res. 2017;18:113.
[CrossRef] [Google Scholar]

[9] Cordoba-Lanus E, Cazorla-Rivero S, Espinoza-Jimenez A, de-Torres JP, Pajares MJ, Aguirre-Jaime A, Celli B, Casanova C. Telomere shortening and accelerated aging in COPD: Findings from the BODE cohort. Respir Res. 2017;18:59.
[CrossRef] [Google Scholar]

[10] Liu Z, Zhang J, Yan J, Wang Y, Li Y. Leucocyte telomere shortening in relation to newly diagnosed type 2 diabetic patients with depression. Oxid Med Cell Longev. 2014;2014:673959.
[CrossRef] [Google Scholar]

[11] Ping F, Li ZY, Lv K, Zhou MC, Dong YX, Sun Q, Li YX. Deoxyribonucleic acid telomere length shortening can predict the incidence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. J Diabetes Investig. 2017;8:174-80.
[CrossRef] [Google Scholar]

[12] Tajbakhsh S, Aliakbari K, Hussey DJ, Lower KM, Donato AJ, Sokoya EM. Differential telomere shortening in blood versus arteries in an animal model of type 2 diabetes. J Diabetes Res. 2015;2015:153829.
[CrossRef] [Google Scholar]

[13] Hammadah M, Al M.I, Wilmot K, Ramadan R, Abdelhadi N, Alkhoder A, Obideen M, Pimple PM, Levantsevych O, Kelli HM, Shah A, Sun YV, Pearce B, Kutner M, Long Q, Ward L, Ko YA, Hosny MK, Lin J, Zhao J, Bremner JD, Kim J, Waller EK, Raggi P, Sheps D, Quyyumi AA, Vaccarino V. Telomere shortening, regenerative capacity, and cardiovascular outcomes. Circ Res. 2017;120:1130-8. CIRCRESAHA.116.309421 [pii]
[CrossRef] [Google Scholar]

[14] Baragetti A, Palmen J, Garlaschelli K, Grigore L, Pellegatta F, Tragni E, Catapano AL, Humphries SE, Norata GD, Talmud PJ. Telomere shortening over 6 years is associated with increased subclinical carotid vascular damage and worse cardiovascular prognosis in the general population. J Intern Med. 2015;277:478-87.
[CrossRef] [Google Scholar]

[15] Chang AC, Ong SG, LaGory EL, Kraft PE, Giaccia AJ, Wu JC, Blau HM. Telomere shortening and metabolic com-promise underlie dystrophic cardiomyopathy. Proc Natl Acad Sci USA. 2016;113:13120-5. 1615340113 [pii]
[CrossRef] [Google Scholar]

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Telomere Length Alterations Associated with Breast, Thyroid and Cervical Cancers

Abstract

Keywords

Biomarker

Breast Cancer

Cervical Cancer

Telomere

Telomeric Shortening

Telomerase

Thyroid Cancer

Introduction

Telomeres as Biomarkers

Breast Cancer

Genetic Polymorphisms in Breast Cancer

Thyroid Cancer

Cervical Cancer

Conclusion

Conflict of Interest

References

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